Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
  • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

• Triterpenoids are biosynthesized in plants by the cyclization of squalene. Although candidates for medicinal use, these naturally occurring molecules display relatively weak biological activity. Accordingly, chemists have sought to synthesize analogues of enhanced potency (Honda et al, 1997 & 1998).
• CDDO 2-cyano-3,12-dioxoleana- 1,9(1 1 )-dien-28-oate
• Bore et al. (2002) determined a crystal structure. In that form, which is hydrated, water coordinates interactions that engender a particular crystal packing and structure.
• a non-hydrous crystalline form of CDDO methyl ester is provided.
• the invention also contemplates a pharmaceutical composition in solid dosage form, comprising (i) a therapeutically effective amount of a non-hydrous crystalline form of CDDO methyl ester with (ii) an edible carrier.
• the present invention is embodied in a glassy solid form of CDDO methyl ester, having an x-ray powder diffraction pattern with a halo peak at approximately 13.5 °2 ⁇ , as shown in Figure 2C, and a glass transition temperature (T g ).
• T g glass transition temperature
• the T g can range from about 120°C to about 135°C. In other embodiments, the Tg ranges from about 125°C to about 13O 0 C.
• the glassy solid form of CDDO-methyl ester can have a PDF spectrum with similar peaks to Figure 28 from about 5 A to about 20 A.
• the invention provides a pharmaceutical composition in solid dosage form, comprising (i) a therapeutically effective amount of a glassy solid form of CDDO methyl ester with (ii) an edible carrier.
• the invention contemplates a methodology for treating a cancer patient, comprising: administering such a pharmaceutical composition to a cancer patient.
• the invention also contemplates administering the glassy form of CDDO-methyl ester in combination with another anti-cancer drug.
• the anti-cancer drug may be gemcitabine and the cancer may be pancreatic cancer.
• the invention encompasses as well a methodology for the treatment of diseases or disorders that involve acute or chronic oxidative stress and inflammation, particularly those characterized in part by overexpression of inducible nitric oxide synthase (iNOS) or inducible cyclooxygenase- (COX-2).
• iNOS inducible nitric oxide synthase
• COX-2 inducible cyclooxygenase-
• the invention is drawn to a dimethanol solvate form of CDDO-methyl ester, having an x-ray powder diffraction pattern with characteristic peaks as shown in Table 18 and a DSC pattern as shown in Figure 24.
• the dimethanol solvate form may be used as an intermediate for the production of a glassy solid form of CDDO methyl ester.
• a method for the production of the glassy solid form of CDDO-methyl ester, via the dimethanol solvate form comprises preparing a dimethanol solvate form of CDDO-methyl ester and drying the dimethanol solvate form.
• the invention is drawn to a method of growing a crystal of CDDO methyl ester dimethanolate, comprising preparing a solution of purified CDDO methyl ester in warm anhydrous methanol, adding the warm solution to a vessel of chilled methanol, and filtering the resulting crystals.
• the invention is drawn to a pharmaceutical composition
• a pharmaceutical composition comprising (i) a therapeutically effective amount of CDDO- methyl ester and (ii) an excipient that is a glass former, such that the composition has a T g .
• the excipient may be selected, for instance, from the group consisting of (A) a carbohydrate, carbohydrate derivative, or carbohydrate polymer, (B) a synthetic organic polymer, (C) an organic acid salt, (D) a protein, polypeptide, or peptide, and (E) a high molecular weight polysaccharide.
• Illustrative of the class of synthetic organic polymer excipients are a hydroxpropyl methyl cellulose, such as hydroxpropyl methyl cellulose phthalate ester, a poly[l-(2-oxo-l-pyrrolidi ⁇ yl)ethylene or copolymer thereof, such as PVP/VA, and a methacrylic acid copolymer, such as methacrylic acid - ethyl acrylate copolymer (1 :1).
• copovidone which is l-vinyl-2- pyrrolidone - vinyl acetate copolymer (3:2).
• Figure 1 depicts the chemical structure of CDDO methyl ester.
• Figure 2 presents the XRPD pattern of Form A (top) and Form B (bottom). From top to bottom: unmicronized Form A; micronized Form A; and Form B.
• Figure 3 shows the DSC and TG curve of CDDO methyl ester (Form A).
• Figure 4 shows the hot stage analysis of Form A - unmicronized.
• Figure 5 shows the dynamic vapor sorption isotherm of Form A - unmicronized.
• Figure 6 shows the SEM images of Form A - unmicronized.
• Figure 7 shows Form A before (top) and after (bottom) stress at 195°C.
• Figure 8 shows the NMR spectrum of Form A - unmicronized.
• Figure 9 shows the MDSC curve of Form B CDDO methyl ester.
• Figure 10 shows Form B CDDO methyl ester before (top) and after (bottom) thermal stress at 200° C/ambient RH for 60 minutes.
• Figure 1 1 shows the NMR spectrum of Form B CDDO methyl ester.
• Figure 12 shows an ORTEP drawing of a single Form A molecule with labeling.
• Atoms are represented by 50% probability anisotropic thermal ellipsoids.
• Figure 13 shows an ORTEP drawing of the contents of the asymmetric unit of
• Atoms are represented by 50% probability anisotropic thermal ellipsoids.
• Figure 14 shows a packing diagram of Form A crystals viewed down the crystal lographic a axis.
• Figure 15 shows a packing diagram of Form A crystals viewed down the crystal lographic b axis.
• Figure 16 shows a packing diagram of Form A crystals viewed down the crystallographic c axis.
• Figure 17 shows the calculated X-ray powder pattern of Form A
• Figure 18 shows the experimental XRPD of Form A.
• Figure 19 presents a comparison of the calculated and experimental XRPD patterns for Form A CDDO methyl ester.
• Figure 20 shows a representative plot of the area under the curve for Form A
• Form B following a 4.1 mg/kg oral administration to cynomolgus monkeys.
• Each datum point represents the mean plasma concentration of CDDO methyl ester in 8 animals. Error bars represent the standard deviation within the sampled population.
• Figure 21 shows a comparison of plasma concentration of Form B CDDO methyl ester versus Form A in Animal #5O5M (top panel) and animal #507F (bottom panel).
• Figure 22 presents a comparison of plasma concentration of Form B CDDO methyl ester versus Form A between Animal #508F (top panel) and animal #502M (bottom panel).
• Figure 23 depicts thermograms of CDDO methyl ester hemibenzene solvate.
• Figure 24 shows thermograms of CDDO-methyl ester dimethanol solvate.
• Figure 25 depicts TGIR data relating to CDDO methyl ester dimethanol solvate.
• Figure 26 presents XRPD patterns of CDDO methyl ester dimethanol solvate, before (top) and after (bottom) TGIR analysis (up to 140°C).
• Figure 27 is an overlay representation of PDF data for Form A vs. Form B Local order is similar from about 5 A to about 20 A.
• Figure 28 is an overlay representation of X-ray amorphous patterns for different preparations of Form B, showing substantial uniformity among the preparations.
• Figure 29 is a schematic representation of space group P4 3 2i2 (#96).
• Figure 30 shows the mean blood concentrations of CDDO-methyl ester following single oral administrations of CDDO-methyl ester capsules to male Cynomolgus monkeys
• CDDO methyl ester To realize the therapeutic potential of CDDO methyl ester, depicted in Figure 1 (chemical structure) and in Figure 12 (ORTEP drawing), the present inventors investigated other forms of the compound that possessed properties, such as greater aqueous solubility and chemical stability, that are advantageous to development of a medicinal product with suitable pharmacokinetics. Consequently, the inventors discovered two forms of CDDO methyl ester, distinct from the crystal form elucidated by Bore et al. (2002), that have such properties and, hence, are candidates for drug development in their own right.
• Table 10 below enumerates additional crystal data for Form A, along with crystallographic data-collection parameters.
• Form B is in a single phase but lacks such a defined crystal structure. Rather, Form B is typified by an x-ray powder diffraction (XRPD) spectrum differing from that of Form A (see Figure 2, inter alia). Moreover, Form B displays a bioavailability that is surprisingly better than that of Form A (see Example 7).
• Methodology for the synthesis of CDDO methyl ester has been published. See U.S. patent No. 6,326,507, Honda et al. (1998), and Honda et al. (2000).
• Form A and Form B of CDDO methyl ester are readily prepared from a variety of solutions of the compound, illustrated by those detailed in Table 3-5, infra.
• Form B can be prepared by fast evaporation or slow evaporation in MTBE, THF, toluene, or ethyl acetate.
• Form A can be prepared via fast evaporation, slow evaporation, or slow cooling of a CDDO methyl ester solution in ethanol or methanol.
• Preparations of CDDO methyl ester in acetone can produce either Form A, using fast evaporation, or Form B, using slow evaporation. Additional preparation methods are described below, including the tables provided there.
• Form B Since it does not have a defined crystal structure, Form B likewise lacks distinct
• XRPD peaks such as those that typify Form A, and instead is characterized by a general
• Form B is a "glassy" material: As shown by the PDF, the nearest neighbor atom-atom interactions match that observed for crystalline Form A, but the notion of an average unit cell does not apply because there is no long-range order manifested.
• samples of Form B show no long-range molecular correlation, i.e., above roughly 20 A (see Figure 27). Moreover, thermal analysis of Form B. samples reveals a glass transition temperature (T g ). In contrast, a disordered nanocrystalline material, does not display a T g but instead only a melting temperature (T m ), above which crystalline structure becomes a liquid.
• T g glass transition temperature
• T m melting temperature
• the present description also characterizes a CDDO-methyl ester dimethanol solvate form that can be used to prepare form B (see Example 9). Also characterized here is a CDDO-methyl ester hemibenzenate form (see Example 8).
• the properties of the inventive CDDO methyl ester forms are both distinctive, as mentioned above, and conducive to their use as medicinal agents.
• the bioavailability of Form B and Form A CDDO methyl ester varied in monkeys when the monkeys received equivalent dosages of the two forms orally, in gelatin capsules. See Example 7.
• the stability of the newly identified CDDO-methyl ester forms will be useful in the production of pharmaceutical compositions.
• CDDO methyl ester dispersions that retain "x- ray amorphous" character, as described in greater detail below, can be distinguished from dispersions containing crystalline Form A CDDO methyl ester by a variety of techniques, including XRPD and DSC analysis.
• dispersions containing Form A crystalline CDDO methyl ester typically display discrete peaks characteristic of the pure Form A CDDO methyl ester, particularly those that occur at approximately 13.35 and 8.78 (°2 ⁇ ) (for example, see Table 17, infra).
• CDDO methyl ester polymer excipient dispersion of the invention are both distinctive and conducive to their use as medical agents.
• formulations containing CDDO methyl polymer excipient dispersions produced surprising further enhancements in bioavailability, even relative to formulations produced from pure Form B CDDO methyl ester.
• this description uses the terms “about” or “approximately” to indicate variations in data used to describe the CDDO-methyl ester forms.
• a melting temperature may vary based on instrumentation or conditions.
• the USP ⁇ 891> states that "In the case of melting, both an "onset” and a “peak” temperature can be determined objectively and reproducibly, often to within a few tenths of a degree.” Practical experience indicates this is not true for measuring the T g of a material.
• the T g will depend on many factors: how the sample was prepared, the thermal history of the sample (relaxation), residual solvent that may or may not volatilize prior to T g , the instrument, sample preparation (sample mass, particle size, packing, diluents), the parameters used to measure T g (particularly scan rate), the parameters used to determine the location of the T g (onset temperature, mid-point temperature, inflection point temperature, or offset temperature), whether a relaxation endotherm is present at T g , and other factors. Some factors will decrease T g (plasticization due to residual water/solvent), while others will increase T g (faster scan rate, relaxation) and may do so by as much as 10-15 0 C. The change in heat capacity at T g ( ⁇ Cp) can be important, as reported by Zhou et al., J. Pharmaceutical Sciences 91 : 1863-72 (2002).
• the present description speaks of different patterns in terms of their "characteristic" peaks.
• the assemblage or group of such peaks is unique to a given polymorphic form, within the uncertainty attributable to individual instruments and to experimental conditions, respectively.
• the XRPD pattern of the glassy material shows a broad halo peak at approximately 13.5 °2 ⁇ , which appears to be characteristic of Form B.
• Other halos are not as well-defined, and the shape/position of this pattern may change as a function of the instrument and experimental conditions. Variation in the position of this broad peak will be larger than that of the characteristic peaks of the respectively crystalline forms. In particular, variability of up to ⁇ °2 ⁇ for the broad peak of Form B can be expected in certain instruments.
• the XRPD pattern of glassy materials produced as CDDO methyl ester excipient dispersions also show a broad halo peak, typically centered at approximately 13.5 °2 ⁇ . These materials likewise display a T g by modulated Differential Scanning Calorimetry (mDSC). Similar to pure Form B CDDO methyl ester samples, the shape and position of the XRPD pattern for an excipient dispersion may change as a function of the instrument used, the experimental conditions, and the specific excipient employed to produce the dispersions.
• the present invention further relates to the use of Form A, Form B, and glassy, XRPD-amorphous excipient dispersions of CDDO methyl ester, respectively, for treating diseases associated with inflammation, including a cancerous condition and various pathologies affecting the central nervous system.
• treatment of these diseases comprises administering to a subject in need thereof an effective amount of the novel CDDO methyl ester forms enumerated here.
• AD Alzheimer's disease
• PD Parkinson's disease
• MS multiple sclerosis
• ALS amyotrophic lateral sclerosis
• RA rheumatoid arthritis
• other autoimmune diseases inflammatory bowel disease, and other pathological conditions tied to excessive production of either nitric oxide or prostaglandins.
• COX-2 The functional relevance of COX-2 to intestinal tumorigenesis has been demonstrated by knockout of the COX-2 gene (Oshima et al., 1996). Mice bearing this knockout were mated with polyp-forming mice bearing lesions in the APC gene; the COX-2 knockout caused a dramatic diminution in the number of polyps in the offspring. Furthermore, treatment of experimental animals with either selective COX-2 inhibitors or non-selective COX-I /COX-2 inhibitors has been reported to be a potent approach to chemoprevention of intestinal cancer (Marnett, 1992; Oshima et al., 1996; Boolbol et al., 1996; Reddy et al, 1996; Sheng et al, 1997).
• iNOS As for the role of iNOS in carcinogenesis, it is clear that NO is a potent mutagen (Tamir and Tannebaum, 1996), and that nitric oxide can also activate COX-2 (Salvemini et ai, 1993, 1994). There also is a marked increase in iNOS in rat colon tumors induced by the carcinogen, azoxymethane (Takahashi et ai, 1997). Similarly, overexpression of iNOS in human tumors has been reported as a negative prognostic factor (e.g., Ekemekcioglu et ai, 2006).
• Inflammatory signaling pathways and other disease-associated signaling pathways such as are induced by angiotensin II, frequently stimulate excessive production of reactive oxygen or nitrogen species (RONS), including superoxide, hydrogen peroxide, nitric oxide and peroxynitrite.
• RATS reactive oxygen or nitrogen species
• CDDO methyl ester has been shown to be a potent inducer of antioxidant activity and a potent inhibitor of inflammatory processes in many different cell types (Dinkova-Kostova et ai, 2005; Liby et ai, 2006; Ahmad et ai, 2006; Shishodia et ai, 2006).
• autoimmune diseases e.g., rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis
• cardiovascular diseases e.g., atherosclerosis and heart failure
• diabetes type I and type II
• respiratory diseases e.g., chronic obstructive pulmonary disease and asthma
• chronic kidney disease renal failure, liver failure, and pain syndromes (e.g., neuropathic pain, fibromyalgia, and migraine).
• triterpenoids have been shown to inhibit the replication of HIV-I in macrophages (Vazquez et ai, 2005) and so may be useful in the treatment of viral diseases, particularly those in which significant morbidity is caused by organ or tissue inflammation (e.g., viral hepatitis, influenza, herpes simplex).
• organ or tissue inflammation e.g., viral hepatitis, influenza, herpes simplex.
• MS is known to be an inflammatory condition of the central nervous system (Williams, Ulvestad and Hickey, 1994; Merrill and Beneviste, 1996; Genain and Nauser, 1997). Inflammatory, oxidative, or immune mechanisms may be involved in the pathogenesis of MS, AD, PD, and ALS (Bagasra et ai, 1995; Griffin et ai, 1995; McGeer and McGeer, 1995; Good et ai, 1996; Simonian and Coyle, 1996; Kaltschmidt et ai, 1997).
• Both reactive astrocytes and activated microglia have been implicated in causation of NDD/NID; there has been a particular emphasis on microglia as cells that synthesize both NO and prostaglandins as products of the respective enzymes, iNOS and COX-2. De novo formation of these enzymes may be driven by inflammatory cytokines such as interferon- gamma or interleukin-1.
• CDDO-Me has demonstrated an ability to inhibit the expression of COX-2 and iNOS, enzymes associated with both inflammation and carcinogenesis.
• CDDO-Me also was shown to inhibit the activation of nuclear factor-kappa B (NF- ⁇ B) and Signal Transducer and Activator of Transcription 3 (STAT3), transcription factors associated with inflammation, tumor progression, and tumor resistance to therapy.
• NF- ⁇ B nuclear factor-kappa B
• STAT3 Signal Transducer and Activator of Transcription 3
• CDDO-Me effectively inhibited the growth of tumors formed by human tumor cell lines implanted in rodents or syngeneic cancer cell lines implanted in rodents (Table 16).
• Doses used in these studies were generally in the range of 10 to 100 mg/kg/day, depending on the species, strain, and method of administration.
• the present invention encompasses stable, controlled release dosage forms containing a CDDO methyl ester form.
• a dosage form of the invention can be for once-per-day administration, for delayed release, or for pulsatile release, thereby to optimize therapy by matching pharmacokinetic performance with pharmacodynamic requirements.
• Form B Any of Form B, Form A, and formulations containing excipient dispersions of CDDO methyl ester may be administered orally.
• the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound.
• Other modes of administration such as topical, subcutaneous, intravenous, and intraperitoneal are also part of the current invention.
• Form B or Form A CDDO methyl ester may be administered to a subject in an appropriate carrier, such as liposomes, or in a diluent.
• suitable diluents include saline and aqueous buffer solutions.
• Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes. See, e.g., Strejan et ai, J. Neuroimmunol. 7: 27(1984).
• the therapeutic compound can be administered orally, with inert diluents, additives, or an edible carrier, to form a pharmaceutical composition.
• the therapeutic compound of the invention with other ingredients, may be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
• Form A or Form B may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• an excipient dispersion of the present invention may be presented in a variety of dosage form types, including those described here for Form A or Form B.
• the percentage of the therapeutic compound in the compositions and preparations may be varied, in accordance with conventional practice, to effect a suitable dosage of the active agent.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of Form B CDDO methyl ester or Form A, in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and, if desired, other active ingredients.
• the active compound can be produced as a homogeneous excipient dispersion, starting from either Form B or Form A.
• Such a CDDO methyl ester excipient dispersion is a solid solution and can be viewed as a homogeneous dispersion at the molecular level.
• Such dispersions can be advantageously formulated together with other pharmaceutically acceptable additives, to stabilize the active compound and, in some instances, to provide further improvements in bioavailability.
• the choice of an excipient for the dispersion is guided by the criteria that the excipient be both a good "glass former" and pharmaceutically acceptable. More generally, the excipient should form a stable, homogeneous glassy matrix, which stabilizes the dispersion by affording a T g that is above typical, ambient temperature storage conditions.
• An additional criterion in this regard is that the excipient used for the dispersion should be chemically compatible with other additives, such as binders, fillers, lubricants, glidants, and the like, which may be employed in the final formulation to confer desired functional properties.
• an excipient can be selected, pursuant to the invention, from a number of compounds characterized by suitably high T g values, such as (A) carbohydrates, carbohydrate derivatives, and carbohydrate polymers, (B) synthetic organic polymers, (C) organic acid salts, (D) proteins, polypeptides, and peptides, and (E) high molecular weight polysaccharides such as heparin, which is a sulfated polysaccharide, and hyaluronic acid, a mucopolysaccharide.
• T g values such as (A) carbohydrates, carbohydrate derivatives, and carbohydrate polymers, (B) synthetic organic polymers, (C) organic acid salts, (D) proteins, polypeptides, and peptides, and (E) high molecular weight polysaccharides such as heparin, which is a sulfated polysaccharide, and hyaluronic acid, a mucopolysaccharide.
• class (A) Illustrative of class (A) are: cellulose derivatives, such as hydroxypropyl cellulose (HPC), hydroxpropyl methyl cellulose (HPMC), and ethyl cellulose; polysaccharides, such as raffinose, maltotriose, stachyose, dextrins (including maltodextrins and cyclodextrins, inter alia), dextrans, and soluble starch; alditols, such as mannitol, xylitol, and sorbitol; and disaccharides, such as lactose, trehalose, maltose, and sucrose.
• a preferred excipient from this class is hydroxypropyl methyl cellulose phthalic ester (HPMC-P).
• Class (B) is exemplified by poly[l-(2-oxo-l-pyrrolidinyl)ethylene, a/k/a povidone or polyvinylpyrrolidone (PVP) and related co-polymers, such as PVP/VA, of varying molecular weights. Also included in this class is the methacrylic acid family of copolymers, such as methacrylic acid copolymer Type C (USP/NF).
• Class (C) is illustrated by salts, such as sodium, potassium, calcium and magnesium salts, of lactic acid, ascorbic acid, maleic acid, oxalic acid, malonic acid, malic acid, succinic acid, citric acid, gluconic acid, and glutamic acid, respectively.
• representative salts in this regard are sodium citrate, sodium lactate, sodium maleate, magnesium gluconate, and sodium ascorbate.
• Exemplary class (D) excipients are: human serum albumin; a polyamino acid, e.g., polyalanine, polyarginine, polyglycine, and polyglutamic acid; casein; collagen; gelatin and purified gelatin proteins; and certain pharmacologically active compounds, such as insulin.
• a polyamino acid e.g., polyalanine, polyarginine, polyglycine, and polyglutamic acid
• casein casein
• collagen collagen
• gelatin and purified gelatin proteins certain pharmacologically active compounds, such as insulin.
• Excipients can alter some of the physical characteristics of the pharmaceutical formulations, as noted. For instance, dispersion within the various polymeric excipients may lead to a reduction in the observed T g of the formulation. Normally, T g is an additive property based on proportions of materials involved. Accordingly, when utilizing polymers with T g values that are less than that of the amorphous Form B, there is an expectation of a reduction in observed T g for the dispersions (mixtures). Additionally, moisture or traces of residual organic solvent often are present, which tends to reduce T g as well. For purposes of generating a solid CDDO-Me dispersion, the optimal choice of excipient typically must be determined empirically.
• Methods can vary for preparing homogenous, glassy, X-ray amorphous dispersions of CDDO-Me with pharmaceutically acceptable excipients, and the examples presented here utilize spray drying to generate such dispersions.
• Other methods of manufacture may be used to produce dispersions of the invention with equivalent properties and utility. See Repka et ai, 2002, and references cited therein. Such other methods include but are not limited to solvent evaporation and extrusion, such as hot melt extrusion.
• the administered quantity of the compound or composition of the present invention will vary, depending on the patient and the mode of administration, and can be any effective amount.
• a given treatment regimen for the administration of a composition of the present invention can be developed by way of normal and routine pre-clinical and clinical testing, the details of which are a function of the therapeutic indication, among other factors.
• the quantity of the active agent administered may vary over a wide range, thereby to provide, in a unit dosage, a pharmacologically effective amount based upon the body weight of the patient per day, to achieve the desired effect.
• the desired dosage may also vary according to the condition being treated. For example, treatment of acute cancer may require a significantly higher dose than treatment of an inflammatory condition such as arthritis.
• a composition of the present invention is presented as a unit dose and taken preferably from 1 to 3 times daily, most preferably once daily to achieve the desired effect.
• compositions of the current invention may be taken every two days, every three days, every four days,, every five days, every six days, or once a week.
• the compositions of the current invention also may be administered alone or in combination with other drugs based on the particular needs of a patient.
• the compositions of the current invention may be administered with anti-cancer agents as part of a treatment regimen.
• CDDO-methyl ester may be administered with gemcitabine, or other agents, during the treatment of a cancer, such as pancreatic cancer.
• pharmaceutical compositions of the invention are prepared using conventional materials and techniques, such as mixing, blending and the like.
• a medicament containing Form A or Form B also can contain other components, including but not limited to suitable adjuvants, carriers, excipients, and stabilizers, etc.
• a therapeutic formulation of the invention is preferably a solid but, in principle, could be a liquid, such as a suspension or emulsion.
• the oral maintenance dose typically is between about 0.1 mg and about 1000 mg, preferably given once daily.
• the dosage may be varied or keyed to a subjects weight. Typical dosages may be from about 0.01 mg/kg to 100 mg/kg, with the preferred unit dosage forms including tablets and capsules.
• the following examples are illustrative only and are not intended to limit the present invention. The materials and methods employed in the examples are outlined below: a. Materials
• thermodynamic and kinetic crystallization techniques were employed. These techniques are described in more detail below. Once solid samples were harvested from crystallization attempts, they were either examined under a microscope for morphology or observed with the naked eye. Any crystalline shape was noted, but sometimes the solid exhibited unknown morphology, due to small particle size. Solid samples were then analyzed by XRPD, and the patterns were compared to each other to identify new crystalline or noncrystalline forms.
• Solutions were prepared in various solvents at elevated temperature. The solutions were then filtered through a 0.2- ⁇ m nylon or PTFE filter into an antisolvent at sub-room temperature. The presence or absence of solids was noted. If there were no solids present, or if the amount of solids was judged too small for XRPD analysis, the vial was placed in a freezer. The resulting solids were isolated by filtration and dried prior to analysis.
• Solutions were prepared in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2- ⁇ m nylon filter. The filtered solution was allowed to evaporate at room temperature in an uncapped vial. The solids that formed were isolated and analyzed.
• 1,4-dioxane solutions were prepared, filtered through a 0.2- ⁇ m nylon filter, and frozen using dry ice.
• the frozen sample was lyophilized using an FTSsystems Flexi-Dry. The lyophilization temperature was not controlled.
• Micronization of materials can be accomplished in fluid energy mills and can reduce particle size to 1 to 20 microns. Further description of these processes can be found in PERRY'S CHEMICAL ENGINEERS' HANDBOOK, 7 th ed. (McGraw Hill, 1998).
• a solid sample was placed into a stainless steel milling rotor with a small metal ball. Some samples had a small amount of water added (wet grinding). The sample was then ground at 30 Hz on a Retesh type MM220 mixermill for approximately 20 minutes. The resulting solids were isolated and analyzed.
• a solid sample was placed into a stainless steel grinding jar with a grinding rod. The sample was then ground at 15 Hz on a SPEX Certiprep model 6750 cryomill for a set amount of time. The grinding jar was submerged in a bath of liquid nitrogen during the experiment. The solids were isolated and analyzed.
• a solid sample was placed on a glass microscope slide and leveled. The slide was then placed on a hot plate at a set temperature until the solid melted. Upon melting, the slide was removed from the hot plate and placed on a cold counter top to cool quickly. The resulting solids were dried under nitrogen and analyzed.
• Solutions were prepared in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2- ⁇ m nylon filter. The filtered solution was allowed to evaporate at room temperature or under nitrogen in a vial covered with aluminum foil perforated with pinholes. The solids thus formed were isolated and analyzed.
• Solutions were prepared by adding enough solids to a given solvent so that excess solids were present. The mixture was then agitated in a sealed vial at room temperature. After either 7 or 10 days, the solids were isolated by vacuum filtration and analyzed.
• a saturated solution of CDDO methyl ester was prepared in methanol at ⁇ 60°C and filtered through a 0.2- ⁇ m filter into an open vial while still warm. The vial was covered and allowed to cool slowly to room temperature. The presence of pyramidal tablets was observed after 1 day.
• the standard deviation of an observation of unit weight was 1.05.
• the highest peak in the final difference Fourier had a height of 0.22 e/A3.
• the minimum negative peak had a height of -0.25 e/A 3 .
• a calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 [6] and the atomic coordinates, space group, and unit cell parameters from the single crystal data.
• ORTEP diagram was prepared using ORTEP III [7][9]. Atoms are represented by 50% probability anisotropic thermal ellipsoids. Packing diagrams were prepared using CAMERON [8] modeling software. Additional figures and BFDH mo ⁇ hology predictions were generated using Mercury 1.4.1 [4]. c. Instrumental Techniques i. Differential Scanning Calorimetry (DSC)
• Moisture sorption/desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. Sorption and desorption data were collected over a range of 5% to 95% relative humidity (RH) at 10% RH intervals under a nitrogen purge. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.010 % weight change in 5 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. Sodium chloride and polyvinypyrrolidine were used as calibration standards. iii. Karl Fischer (KF)
• Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. Samples were observed using a 2Ox objective (obj.) with cross polarizers (CP) and lambda ( ⁇ ) compensator. Samples were placed on a coverslip. A second coverslip was then placed over the sample. Each sample was visually observed as the stage was heated. Images were captured using a SPOT InsightTM color digital camera with SPOT Software v. 4.5.9. The hot stage was calibrated using USP melting point standards. v. Modulated Differential Scanning Calorimetry (MDSC)
• Modulated differential scanning calorimetry data were obtained on a TA Instruments differential scanning calorimeter equipped with a refrigerated cooling system (RCS). The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and crimped. MDSC data were obtained using a modulation amplitude of +/- 0.8 0 C and a 60 second period with an underlying heating rate of 2°C/min from -25 to 250°C. The temperature and the heat capacity were calibrated using indium metal and sapphire as the calibration standards, respectively. The reported glass transition temperature is obtained from the inflection of the step change in the reversible heat flow versus temperature curve. vi. Nuclear Magnetic Resonance (NMR)
• X-ray powder diffraction analyses were also performed on an Inel XRG-3000 diffractometer, equipped with a curved position-sensitive detector with a 2 ⁇ range of 120°.
• Real time data was collected using Cu Ka radiation at a resolution of 0.03°2#.
• the tube voltage and amperage were set to 40 kV and 30 mA, respectively. Patterns are displayed from 2.5 to 40°20 to facilitate direct pattern comparisons.
• Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. Instrument calibration was performed daily using a silicon reference standard, d. Additional Calculation Techniques i. PDF
• PDF Pair Distribution Function
• Measurement conditions are used to minimize the background in the x-ray patterns and algorithms are used to calculate the PDF from measured x-ray data.
• the PDFs were calculated using PatternMatch v2.2.1, using the entire range of measured data for all samples.
• Form A was observed from approximately 50% of the samples.
• the formation of Form A was not limited to a particular crystallization condition and was prepared from a variety of different experiments and solvents.
• Form B material was prepared from lyophilization, melt/quench, and several evaporation experiments.
• Example 3 Characterization of CDDO-methyl ester - Form A (unmicronized) [0131] Form A is unsolvated (Table 6). The single crystal structure of Form A was determined based on methods described above. Crystals of CDDO-methyl ester were grown and submitted for single crystal structure analysis. The crystal structure was determined by single crystal X-ray diffraction. The proposed structure of CDDO-methyl ester is shown in Figure 1.
• the space group was determined to be P4i2 ⁇ 2 (no. 96).
• Table 10 A summary of the crystal data and crystallographic data collection parameters is provided in Table 10.
• FIG. 12 An ORTEP drawing of a single CDDO methyl ester molecule is shown in Figure 12.
• the asymmetric unit shown in Figure 13 contains three CDDO methyl ester molecules.
• the molecules are the same as the proposed structure from Figure 1.
• Packing diagrams viewed along the a, b, and c crystallographic axes are shown in Figures 14-16, respectively. With no hydrogen bonds, the crystal structure includes numerous van der Waals interactions.
• the view down the crystallographic b axis ( Figure 15) highlights the helical nature of the packing arrangement of the tetragonal screw axis and the predicted BFDH morphology. The predicted morphology is in good agreement with the observed habit of the single crystal used in the data collection.
• the calculated XRPD pattern of CDDO methyl ester, generated from the single crystal data, is provided in Figure 17.
• the experimental XRPD pattern of CDDO methyl ester is shown in Figure 18.
• Characteristic peaks for the Form A XRPD pattern are provided in Table 17.
• a comparison of the calculated and experimental XRPD patterns ( Figure 19) reveals all peaks in the experimental patterns are represented in the calculated XRPD pattern, indicating the bulk material is likely a single phase. The slight consistent shifting observed in peak location is likely due to the fact that the experimental powder pattern was collected at room temperature, and the single crystal data were collected at 15O 0 K. Low temperatures are used in single crystal analysis to improve the quality of the structure.
• CDDO methyl ester Form A the single crystal structure of CDDO methyl ester Form A was determined to confirm to the proposed molecular structure.
• the space group was determined to be P4i2 ⁇ 2 (no. 96).
• the structure of CDDO methyl ester consists of three molecules packed in a helical nature down the crystal lographic b axis. All peaks in the experimental patterns are represented in the calculated XRPD pattern, indicating the bulk material is likely a single phase.
• the thermal data for Form A are shown in Figure 3.
• the DSC curve shows a baseline shift at approximately 157°C and an endotherm with an onset temperature of approximately 222°C (signal maximum at ⁇ 224°C).
• the event at ⁇ 224°C was confirmed as the melt by hot stage microscopy ( Figure 4).
• the thermogravimetry (TG) curve exhibits a negligible weight loss of 0.34% up to 15O 0 C, followed by a weight loss of 1.2% from 150 to
• the DVS data indicate that Form A is not hygroscopic (Figure 5).
• the material shows a negligible weight change throughout the experiment.
• the resulting material was analyzed by XRPD and is Form A.
• Form A is unsolvated and not hygroscopic, therefore, and it melts at approximately 228 0 C, based on observations of analyst during hot stage microscopy.
• Example 4 Characterization of CDDO-methyl ester - Form A (micronized) [0144] Micronized Form A CDDO methyl ester was determined to be Form A by XRPD ( Figure 2, Table 1). Micronized material can be produced by conventional methodology, well known to the field, such as air jet milling. These findings appear to indicate that micronization does not affect Form A in order to alter its XRPD pattern.
• Form B material can be prepared from lyophilization, melt/quench, and several other evaporation experiments, as provided in Table 3.
• the modulated DSC (MDSC) data are shown in Figure 9.
• the reversible curve shows a glass transition temperature (Tg) at approximately 125°C.
• the non-reversible curve shows an exotherm with signal maximum at 195°C and an endotherm with signal maximum at 223°C.
• the non-reversible events are most likely due to crystallization of the Form B material (exotherm) followed by the melt of the crystallized material (endotherm).
• the physical stability of Form B material at various conditions was investigated (Table 9). Samples stressed at 22°C/97% RH, 40°C/ 75% RH, 80°C/0% RH, and 195°C/ambient RH remained Form B.
• Form B is not hygroscopic, crystallizes to Form A at approximately 200 0 C, and has a glass transition temperature (Tg) of approximately 125 0 C - 13O 0 C.
• Form B is not hygroscopic.
• the MDSC data indicates that the glass transition temperature (Tg) of Form B is approximately 125°C - 130 0 C.
• Form B material crystallizes to Form A when stressed at approximately 200 0 C.
• Form B CDDO-methyl ester was subjected to varying stress conditions. Table 15 provides some of the results from these studies.
• Form B samples prepared under varying conditions were analyzed to determine whether they have similar chemical properties. As described above, that is, Form B samples were prepared by cryogrinding, melt quench, and spray drying methods. In addition, unmicronized Form B was micronized to produce micronized Form B. PDF analysis was performed on the samples ( Figure 28), which were determined to be glassy in nature.
• the spray dried powders were analyzed for the level of residual organic solvents, glass transition temperature (T g ) and bulk density. After post-drying the powders were also analyzed for purity, water content, average particle size, absence of crystalline material by X-ray powder diffraction (XRPD) and dissolution profile. [0158] The physiochemical characteristics of the dispersions were evaluated after short term stressing (after 5 days, 40°C / 75% RH) by XRPD and modulated differential scanning calorimetry (mDSC).
• the XRPD profile after stressing continued to be the characteristic halo pattern centered around 13.5 °2 ⁇ , and no peaks associated with the crystalline form were detected.
• Further spray drying studies on two formulation were conducted, using larger scale spray drying equipment. In these cases, a Niro pilot scale dryer model PSD-I (mobile minor 2000) was employed. Also employed were equivalent nozzle and spray drying conditions to those described above. Tables 20 and 21 summarize the solutions prepared for spray drying and their characteristics following spray drying. The formulations showed a lower T g , relative to pure Form B, due to the formulation including polymers with a lower T g than Form B.
• a Retsch ® PIanatory Ball Mill model PM 400 containing zirconia balls of 2 mm average size, was charged with 25 gm of micronized CDDO-Me (average particle size distribution of 6.1 uM), 5 gm of docusate sodium, 1 gm of Tween 80, and 68.3 gm of water. Grinding was initiated at approximately 400 RPM and was continued for 2 hours. A particle size distribution (PSD) determination using a laser light granulometer indicated an average PSD of 0.37 ⁇ M was obtained. To this thick suspension were added 1 gm of microcrystalline cellulose and 0.2 gm of xantham gum, with brief mixing, and the suspension was stored refrigerated.
• PSD particle size distribution
• the ball milled nano suspension was spray coated onto a dry excipient blend in a laboratory scale Aeromatic Strea 1 fluid bed, with the top spray assembly having a pray nozzle size of 0.4 mm.
• the inlet temperature was set at 55 0 C.
• the exhaust temperature range during spraying was 32 to 35°C.
• the resulting granulation was dried for approximately 5 minutes, until the exhaust temperature reached 38°C (Attachment 3-5).
• the composition of the coated materials is given below.
• the crystalline micronized Form A and amorphous, micronized Form B formulations were produced by a conventional dry powder blending process, using, as additives, microcrystalline cellulose, pregelatinized starch, crospovidone (functioning as a disintegrant), colloidal silicon dioxide, and vegetable grade magnesium stearate.
• Micronized CDDO-Me Form A of average PSD 6.1 ⁇ M was used for the Form A formulation, while micronized CDDO-Me Form B of average PSD 10.8 ⁇ M was employed for the corresponding CDDO-Me Form B formulation.
• the table below presents the quantitative composition of both formulations.
• CDDO-Me excipient dispersions described in Example 6 were further formulated by a conventional dry powder blending process, using microcrystalline cellulose, lactose monohydrate, crospovidone (functioning as a disintegrant), and sodium lauryl sulfate as additives.
• the quantitative composition of each formulation appears below. Composition of CDDO-Me excipient dispersions blended with addities in capsule formulation
• Component copolymer Type C 40% PVP/VA 40% HPMC-P
• Gelatin capsule size 2 was used to deliver the formulations in phase 2 and gelatin capsule size 1 was used for delivery in phase 3.
• the net drug content in each capsule was 30 mg, corresponding to a 10 mg/kg dosage of drug, based on an assumption that each monkey weighed 3 kg.
• the capsule was attached to a gavage, the animal was gavaged, and the capsule was released from the end of the gavage by air pressure from an empty syringe.
• a small amount of water (approximately 10 mL) was given orally after the administration of the last capsule.
• CDDO-methyl ester Approximately 100 mg of CDDO-methyl ester was dissolved in 300 ⁇ L of benzene/acetone (10: 1) and filtered through a 0.2- ⁇ m nylon filter. The solution was then sonicated using an ultrasonic processor for 10 minutes and allowed to evaporate at room temperature in an uncapped vial overnight. A clear gel formed and 100 ⁇ L of benzene/acetone (10:1) was added. The solution was submitted to sonication on an ultrasonic processor for approximately 30 minutes. A white precipitate formed. The solids were allowed to air dry.
• Characterization data of the hemibenzenate are summarized in Table 13. Characteristic peaks for the hemibenzenate XRPD pattern are provided in Table 19. The DSC curve exhibits a broad endotherm near 133°C, associated with ⁇ 7.0 % of weight loss in the TG thermograph Figure 23. The weight loss is likely due to the volatilization of benzene (see NMR discussion below), and corresponds to 0.5 moles of benzene for each mole of CDDO-methyl ester. The DSC endotherm observed near 223 0 C most likely results from the melt of desolvated material.
• a CDDO-methyl ester dimethanol solvate was prepared according to the below procedure. Approximately 500 mg of CDDO-methyl ester was dissolved in 20 mL of methanol at 6O 0 C. The solution was then slowly added to 20 mL of cold methanol at -1O 0 C with agitation. White solids were collected by vacuum filtration and then stored in a freezer. [0184] Characterization data are summarized in Table 14. Characteristic peaks for the dimethanolate XRPD pattern are provided in Table 18.
• the DSC curve shows a broad endotherm near 102 0 C, associated with ⁇ 1 1% of weight loss in the TG thermograph ( Figure 24).
• the TGIR data confirms the weight loss is due to volatilization of -2.0 moles of methanol ( Figure 25).
• the resulting material from the TGIR experiment was recovered and was amorphous by XRPD ( Figure 26).
• a baseline shift at approximately 130 0 C, a broad exotherm near 203 0 C followed by a sharp endotherm (onset: 223°C) are also observed in the DSC curve. These events are most likely indicative of the Tg of the amorphous material (Form B) obtained through the desolvation of the dimethanol solvate followed by crystallization of the amorphous material to Form A and melting of that crystalline material.
• CDDO-Me formulated using micronized Form A, was selected for clinical development and first tested in a Phase I safety-oriented study in patients with advanced cancer who had failed to respond adequately to prior therapies.
• CDDO-Me was administered to 21 adult patients with various forms of advanced (metastatic) cancer. Patients were administered daily doses of CDDO-Me capsules at doses ranging from 5 to 900 mg/day (specifically 5, 10, 20, 40, 80, 150, 300, 600, or 900 mg/day).
• CDDO-Me was administered in "cycles" which were repeated until the patient experienced unacceptable toxicity or showed evidence of disease progression. In this study, one cycle of CDDO-Me consisted of 21 consecutive days of dosing followed by a 7-day rest period after which the patient was eligible to start the next cycle.
• CDDO-Me Both the safety and anti-tumor activity of CDDO-Me were reviewed. In addition, the biological effects of CDDO-Me were characterized. CDDO-Me was very well tolerated in these patients, with no significant drug-related adverse events reported. Several patients (approximately 75% of evaluable patients) were considered to have stable disease (based on standard radiological and clinical criteria) at the first evaluation point following completion of the second treatment cycle. Patients who were found to have evidence of progressive disease before completing the second cycle were not formally evaluated, and were not included in the group of evaluable patients. Five patients, including patients with melanoma and renal cell cancer, continued to show stable disease, some with evidence of regression of individual tumor lesions, after four cycles of treatment. Four patients were considered to have stable disease after at least six cycles of treatment. No new metastases developed in any patient receiving a dose of at least 40 mg CDDO-Me per day according to the prescribed schedule.
• circulating inflammatory cytokines were evaluated in patients in the Phase I trial. At doses as low as 5 mg/day, there was a reduction of several circulating pro-inflammatory cytokines and chemokines including MMP-9, TNF ⁇ , IL-8, and VEGF.
• TNF ⁇ which is known to play a significant role in the inflammatory process of diseases such as rheumatoid arthritis, was reduced substantially or to below detectable limits in 3 patients with elevated baseline TNF levels (one patient each at treatment doses of 10, 20, and 40 mg per day).
• phase 2 gene products which include antioxidant and detoxification enzymes, have been monitored in peripheral blood mononuclear cells of patients in the Phase I study. Significant induction of NQOl (NAD(P)H:quinone oxidoreductase), a marker of phase 2 transcriptional activity, has been seen at doses of 10 mg/day and above.
• Tumor biopsy data in several patients also indicated a pronounced degree of tumor cell death after two cycles of treatment with CDDO-Me.
• Levels of serum creatinine were significantly lower on day 21, compared to the pre-treatment baseline level, in more than 80% of the patients in this study. A number of patients who continued on treatment for multiple cycles showed continuing reductions in serum creatinine. Since serum creatinine is a widely used indicator of renal function, these observations indicate that treatment with CDDO-Me improves kidney function.
• Example 12 Crvoground Form A and Form B
• Form A was cryoground and analyzed.
• the measured x-ray data of the sample obtained through cryogrinding (2 hours) showed some broadening in the peak at approximately 13.5°2# PDF analysis of cryoground Form A produced results similar to the Form B analysis. These results suggest that the cryoground Form A is a glassy material and that cryogrinding can provide an alternative method for producing Form B.
• Form B was cryoground and analyzed. The measured x-ray data of the sample obtained through cryogrinding (1 hour) was similar to the starting Form B material. These results indicate that Form B is stable and does not change Form due to cryogrinding.
• Solubilities are calculated based on the total solvent used to give a solution: actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are rounded to the nearest mg/mL. Table 3 - Crystallization Experiments on CDDO methyl ester
• RH relative humidity
• Tg glass transition temperature
• Ambient lab humidity was measured as 74%
• RH c min minor
• Table 10 Crystal Data and Data Collection Parameters for Form A formula C 32 H 43 NO 4 formula weight 505.70 space group P 43 21 2 (No. 96) a, A 14.21620( 10) c ⁇ 81.5875(12) ⁇ , A 3 16488.9(3)
• CDDO- Xenograft (nude rat) CDDO-Me, p.o. 78% TGI 1 Me as effective as radiation
• CDDO-Me outperformed Xenograft (nude mouse) CDDO-Me, i.v. 51% TGI Gemcitabine
• Data presented is from doses at or below the MTD (defined as ⁇ 10% mortality and ⁇ 20% weight loss).

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Molecular Biology (AREA)
• Epidemiology (AREA)
• Immunology (AREA)
• Hospice & Palliative Care (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Steroid Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Glass Compositions (AREA)

Priority Applications (21)

Applications Claiming Priority (2)

Publications (1)

Family

ID=40351005

Family Applications (1)

Country Status (29)

Cited By (43)

Families Citing this family (8)

Citations (3)

Family Cites Families (16)

• 2008
  • 2008-08-13 US US12/191,176 patent/US8088824B2/en active Active
  • 2008-08-14 ES ES12153605.6T patent/ES2602978T3/es active Active
  • 2008-08-14 KR KR1020147002848A patent/KR101544766B1/ko active IP Right Grant
  • 2008-08-14 CN CN2008801112346A patent/CN101820758B/zh active Active
  • 2008-08-14 SG SG10201504650VA patent/SG10201504650VA/en unknown
  • 2008-08-14 TW TW102134576A patent/TWI486357B/zh active
  • 2008-08-14 SI SI200830650T patent/SI2187741T1/sl unknown
  • 2008-08-14 PT PT08795303T patent/PT2187741E/pt unknown
  • 2008-08-14 EP EP12153605.6A patent/EP2450057B1/en active Active
  • 2008-08-14 DK DK08795303.0T patent/DK2187741T3/da active
  • 2008-08-14 PT PT121536056T patent/PT2450057T/pt unknown
  • 2008-08-14 CL CL2008002417A patent/CL2008002417A1/es unknown
  • 2008-08-14 PL PL12153605T patent/PL2450057T3/pl unknown
  • 2008-08-14 CA CA2871864A patent/CA2871864C/en active Active
  • 2008-08-14 EP EP08795303A patent/EP2187741B1/en active Active
  • 2008-08-14 AT AT08795303T patent/ATE549035T1/de active
  • 2008-08-14 KR KR1020107005094A patent/KR101481764B1/ko active IP Right Grant
  • 2008-08-14 PL PL08795303T patent/PL2187741T3/pl unknown
  • 2008-08-14 AU AU2008287388A patent/AU2008287388B2/en active Active
  • 2008-08-14 TW TW097130947A patent/TWI419899B/zh active
  • 2008-08-14 ES ES08795303T patent/ES2382571T3/es active Active
  • 2008-08-14 EA EA201070149A patent/EA018704B1/ru unknown
  • 2008-08-14 NZ NZ583269A patent/NZ583269A/en unknown
  • 2008-08-14 DK DK12153605.6T patent/DK2450057T3/en active
  • 2008-08-14 MX MX2010001628A patent/MX2010001628A/es active IP Right Grant
  • 2008-08-14 SG SG2011094158A patent/SG177905A1/en unknown
  • 2008-08-14 AR ARP080103557A patent/AR073155A1/es unknown
  • 2008-08-14 CN CN201310016448.8A patent/CN103254267B/zh active Active
  • 2008-08-14 WO PCT/US2008/009703 patent/WO2009023232A1/en active Application Filing
  • 2008-08-14 BR BRPI0815540A patent/BRPI0815540A8/pt not_active Application Discontinuation
  • 2008-08-14 HU HUE12153605A patent/HUE031866T2/en unknown
  • 2008-08-14 JP JP2010521031A patent/JP5005812B2/ja active Active
  • 2008-08-14 EA EA201370109A patent/EA023550B1/ru unknown
  • 2008-08-14 SI SI200831728A patent/SI2450057T1/sl unknown
  • 2008-08-14 LT LTEP12153605.6T patent/LT2450057T/lt unknown
  • 2008-08-14 CA CA2696330A patent/CA2696330C/en active Active
• 2010
  • 2010-02-09 IL IL203824A patent/IL203824A/he active IP Right Grant
  • 2010-02-12 ZA ZA201001066A patent/ZA201001066B/xx unknown
  • 2010-10-25 HK HK10110040.7A patent/HK1143537A1/xx unknown
• 2011
  • 2011-11-29 US US13/306,043 patent/US8309601B2/en active Active
• 2012
  • 2012-04-18 HR HRP20120350AT patent/HRP20120350T1/hr unknown
  • 2012-05-23 JP JP2012117773A patent/JP2012188438A/ja active Pending
  • 2012-06-13 CY CY20121100542T patent/CY1112864T1/el unknown
  • 2012-06-29 US US13/537,583 patent/US8633243B2/en active Active
• 2015
  • 2015-05-07 JP JP2015094538A patent/JP2015164939A/ja active Pending
• 2016
  • 2016-11-15 HR HRP20161503TT patent/HRP20161503T1/hr unknown
  • 2016-11-23 CY CY20161101205T patent/CY1118329T1/el unknown
• 2017
  • 2017-03-27 IL IL251419A patent/IL251419A0/he unknown
  • 2017-08-10 JP JP2017154939A patent/JP2018009001A/ja active Pending
• 2020
  • 2020-03-25 AR ARP200100825A patent/AR119704A2/es unknown

Patent Citations (3)

Non-Patent Citations (22)

Also Published As

Similar Documents

Legal Events